Biosynthetic Enzymes of Membrane Glycerophospholipid Diversity as Therapeutic Targets for Drug Development

Valentine, William J.; Hashidate-Yoshida, Tomomi; Yamamoto, Seigo; Shindou, Hideo

doi:10.1007/978-3-030-50621-6_2

Cited by 19 publications

(10 citation statements)

References 140 publications

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“…The latest progress in the development of lipidomics methods established a clear link between alteration of membrane GPL composition and bacterial virulence and antibiotic resistance [14, 34, 66, 67]. Therefore, lipid metabolic enzymes have emerged as an intensively studied class of proteins with the potential for drug targeting [68–71]. For example, the approved antibiotic isoniazid [70] targets the fatty acid biosynthesis enzyme Fabl and daptomycin most likely disturbs the assembly of GPLs in the membrane through interactions with 1-palmitoyl-2-oleoylphosphatidylglycerol.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a bacterial Lands cycle phospholipase A: Structural and mechanistic insights into membrane phospholipid remodeling

Bleffert

Granzin

Caliskan

et al. 2021

Preprint

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Cells steadily adapt their membrane glycerophospholipid (GPL) composition to changing environmental and developmental conditions. While the regulation of membrane homeostasis via GPL synthesis in bacteria has been studied in detail, the mechanisms underlying the controlled degradation of endogenous GPLs remain unknown. Thus far, the function of intracellular phospholipases A (PLAs) in GPL remodeling (Lands cycle) in bacteria is not clearly established. Here, we identified the first cytoplasmic membrane-bound phospholipase A1 (PlaF) from Pseudomonas aeruginosa involved in the Lands cycle. PlaF is an important virulence factor, as the P. aeruginosa ΔplaF mutant showed strongly attenuated virulence in Galleria mellonella and macrophages. We present a 2.0-Å-resolution crystal structure of PlaF, the first structure that reveals homodimerization of a single-pass transmembrane (TM) full-length protein. PlaF dimerization, mediated solely through the intermolecular interactions of TM and juxtamembrane regions, inhibits its activity. A dimerization site and the catalytic sites are linked by an intricate ligand-mediated interaction network which likely explains the product (fatty acid) feedback inhibition observed with the purified PlaF protein. We used molecular dynamics simulations and configurational free energy computations to suggest a model of PlaF activation through a coupled monomerization and tilting of the monomer in the membrane, which constrains the active site cavity into contact with the GPL substrates. Thus, these data show the importance of the GPL remodeling pathway for virulence and pave the way for the development of a novel therapeutic class of antibiotics targeting PlaF-mediated membrane GPL remodeling.

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Section: Discussionmentioning

confidence: 99%

Evidence for a bacterial Lands cycle phospholipase A: Structural and mechanistic insights into membrane phospholipid remodeling

Bleffert

Granzin

Caliskan

et al. 2021

Preprint

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“…AGPATs and MBOATs both engage in modifying fatty chain compositions of membrane glycerophospholipids in the Lands' cycle. 42 By the way, LPCAT1 and LPCAT4 had a strong correlation with each other, indicating their close collaborations.…”

Section: Discussionmentioning

confidence: 90%

Comprehensive Analysis of LPCATs Highlights the Prognostic and Immunological Values of LPCAT1/4 in Hepatocellular Carcinoma

Lin¹,

Zhang²,

Zheng³

et al. 2021

IJGM

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Background:The prognosis of patients with advanced hepatocellular carcinoma (HCC) remains poor. Lipid remodeling modulators are considered promising therapeutic targets of cancers, owing to their functions of facilitating cancer cells' adaption to the limited environment. Lysophosphatidylcholine acyltransferases (LPCATs) are enzymes regulating biomembrane remodeling, whose roles in HCC have not been fully illuminated. Methods: Multiple bioinformatic tools were applied to comprehensively evaluate the expression, genetic alterations, clinical relevance, prognostic values, DNA methylation, biological functions, and correlations with immune infiltration of LPCATs in HCC. Results: We found LPCAT1 was significantly overexpressed and the most frequently altered in HCC. The high-expression of LPCAT1/4 indicated clinicopathological advancements and poor prognoses of HCC patients. Even though the global DNA methylation of LPCATs in HCC showed no significant difference with that in normal liver, the hypermethylation of numerous CpG sites of them implied worse survivals of HCC patients. Thirty LPCATs' interactive genes were identified, which were generally membrane components and partook in phospholipid metabolism pathways. Finally, we found the expression of LPCATs was extensively positively correlated with the infiltration of various stimulatory and suppressive tumor-infiltrating immune cells (TIICs) in the tumor microenvironment. Conclusion:This study addressed LPCAT1/4 were potential prognostic and immunotherapeutic biomarkers of HCC targeting bio-membrane lipid remodeling.

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“…Given the critical role that MBOAT7 plays in the Land's cycle remodeling pathway (Valentine et al, 2020), we also wanted to analyze arachidonic acid-derived oxylipins. When we quantified the WAT levels of > 60 species of oxylipins, none were significantly different between Mboat7 flox/flox control mice and Mboat7 ASKO mice (Figure 2 figure supplement 4).…”

Section: -Figure Supplement 3)mentioning

confidence: 99%

Membrane Bound O-Acyltransferase 7 (MBOAT7)-Driven Lysophosphatidylinositol (LPI) Acylation in Adipocytes Contributes to Systemic Glucose Homeostasis

Massey

Varadharajan

Banerjee

et al. 2022

Preprint

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Non-alcoholic fatty liver disease (NAFLD) is becoming increasingly common and is a leading cause of end stage liver diseases such as cirrhosis and hepatocellular carcinoma. The rise in NAFLD closely parallels the global epidemic of obesity and type 2 diabetes mellitus (T2DM), and there is a clear interrelationship between abnormal lipid metabolism, insulin resistance, and NAFLD progression. Several genetic loci have been identified as contributors to NAFLD progression, all of which are consistently linked to abnormal lipid metabolic processes in the liver. The common loss-of-function variant rs641738 (C>T) near the gene encoding Membrane-Bound O-Acyltransferase 7 (MBOAT7) is associated with increased susceptibility to NAFLD as well as the entire spectrum of NAFLD progression. The MBOAT7 gene encodes a lipid metabolic enzyme that is capable of esterifying polyunsaturated fatty acyl-CoAs to LPI substrates to generate phosphatidylinositol (PI) lipids. We previously showed that antisense oligonucleotide (ASO)-mediated knockdown of Mboat7 in mice promoted high fat diet-induced hepatic steatosis, hyperinsulinemia, and systemic insulin resistance (Helsley et al., 2019). Thereafter, other groups showed that hepatocyte-specific genetic deletion of Mboat7 promoted striking fatty liver and NAFLD progression but does not alter insulin sensitivity, suggesting the potential for cell autonomous roles. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. The expression of Mboat7 in white adipose tissue closely correlates with diet-induced obesity across a panel of ~100 inbred strains of mice fed a high fat/high sucrose diet. Moreover, adipocyte-specific genetic deletion of Mboat7 is sufficient to promote hyperinsulinemia, systemic insulin resistance, and mild fatty liver. Unlike in the liver, where Mboat7 plays a relatively minor role in maintaining arachidonic acid (AA)-containing PI pools, Mboat7 is the major source of AA-containing PI pools in adipose tissue. Our data demonstrate that MBOAT7 is a critical regulator of adipose tissue PI homeostasis, and adipocyte MBOAT7-driven PI biosynthesis is closely linked to hyperinsulinemia and insulin resistance in mice.

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Biosynthetic Enzymes of Membrane Glycerophospholipid Diversity as Therapeutic Targets for Drug Development

Cited by 19 publications

References 140 publications

Evidence for a bacterial Lands cycle phospholipase A: Structural and mechanistic insights into membrane phospholipid remodeling

Evidence for a bacterial Lands cycle phospholipase A: Structural and mechanistic insights into membrane phospholipid remodeling

Comprehensive Analysis of LPCATs Highlights the Prognostic and Immunological Values of LPCAT1/4 in Hepatocellular Carcinoma

Membrane Bound O-Acyltransferase 7 (MBOAT7)-Driven Lysophosphatidylinositol (LPI) Acylation in Adipocytes Contributes to Systemic Glucose Homeostasis

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